Dementia is a devastating clinical syndrome that affects millions of elderly individuals worldwide. Treating patients with dementia is challenging because of the myriad number of pathologies underlying its clinical manifestation and progression. Therefore, it is imperative to better understand the various mechanisms of dementia-inducing diseases in order to correctly diagnose and treat dementia patients. The focus of my proposed project is to study a common, but relatively underappreciated and under-studied, mechanism of dementia characterized by vascular abnormalities, hippocampal shrinkage, and abnormal protein accumulation (TDP-43) in the brain. Our lab has published several studies on two dementia-associated pathologies: hippocampal sclerosis of aging (HS-Aging) and brain arteriolosclerosis (B-ASC). HS-Aging is a common neurodegenerative pathology seen in up to 25% of individuals < 85 years at autopsy. B- ASC is a cerebrovascular pathology that increases in frequency and severity with advanced age. We have identified a common genetic risk variant in the ABCC9 gene with a polymorphism that changes risk for both B-ASC and HS-Aging pathologies. This phenomenon is exciting because it may point the way to a novel future therapeutic intervention related to ABCC9-modulating drugs. As a key step to better understanding the pathogenetic mechanism, new experiments are required. My overall hypothesis is that genetic and pharmacological perturbations in ABCC9 or its gene product lead to B-ASC pathology, which in turn, lead to HS-Aging/TDP-43 resulting in the clinical presentation of dementia. We will address this hypothesis through the following specific aims: 1) Test the hypothesis that a SNP, ABCC9.rs704180, is associated with altered vascular structure in aged individuals and 2) Test the hypothesis that chronic pharmacologic inhibition of ABCC9 gene product will cause B-ASC, thus in turn, exacerbating HS-Aging/TDP-43 pathology. In Aim 1, we will use human tissue samples from the University of Kentucky Alzheimer's Disease Center brain bio-bank to quantify vascular structures in individuals with varying ABCC9 SNP status. In Aim 2, we will treat mice with clinical and pathological HS-Aging characteristics (age-related TDP-43 pathology) to determine the effects of ABCC9 modifying drug treatment in these animals. Successful completion of this project will provide insight into a novel mechanism of dementia. In addition, it will provide opportunities for me to diversify my skillset as I prepare for a future career as a physician-scientist in the field of translational neuroscience research.